Given the remarkable advance in computafional power over the past decade, why has molecular simulation not had a more significant impact on the drug discovery process? While there are certainly noteworthy successes, the impact of virtual screening is limited by approximate treatment of ligand-protein interacfions along ho orthogonal dimensions: (1) Incorporation of backbone flexibility ofthe receptor, and (2) The accuracy with which molecular interacfions are computed at the atomic level. The first Aim seeks a solufion to issue (1) by proposing a novel approach to virtual screening by targefing ensembles of receptor conformafions, as sampled in native like environments during microsecond fimescale simulafion. In contrast to previous efforts, the present proposal suggests a computationally expedient solution to the problem of esfimafing the entropy of binding. The second Aim seeks a solufion to problem (2) by developing a new class of intermolecular potenfial based on recent advances in the quantum mechanical treatment of weak nonbonded interacfions. Previously published results indicate at least a factor of five improvement in accuracy over standard empirical approaches. By bringing these advances to the field of protein-ligand interacfions, dramafic improvement in the accuracy ofthese calculafions is expected. Both Aims will be pursued in the context ofthe A2A adenosine receptor, a member ofthe G-protein coupled receptor family and a target for several disorders ofthe central nervous system, including Parkinson's disease. Hits identified from small molecule libraries will be experimentally validated via a collaboration with a lab with extensive expertise in A2A biochemistry. We will also apply our methods to the opfimizafion of a series of androgen receptor antagonists developed at UD, with the long term goal of treating prostate cancer. Overall, success in either Aim will have a profound and widespread, positive impact on the predictive validity of calculations of small molecule-protein interacfions. This will in turn improve the value of hits identified in virtual screens, and help to realize the predictive promise of virtual screening.